Downregulation of GABAA Receptor Protein Subunits α6, β2, δ, ε, γ2, θ, and ρ2 in Superior Frontal Cortex of Subjects with Autism

Fatemi, S. Hossein; Reutiman, Teri J.; Folsom, Timothy D.; Rustan, Øyvind; Rooney, Robert J.; Thuras, Paul

doi:10.1007/s10803-014-2078-x

Cited by 78 publications

(73 citation statements)

References 74 publications

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“…An E/I imbalance in autism may originate in several ways including increased glutamate activity (25), decreased GABA release (7,8), or decreased numbers of GABA receptors (26). Consistent with the possibility of an E/I imbalance in autism, many of the susceptibility genes may be related to the E/I balance.…”

Section: Significancementioning

confidence: 91%

A computational perspective on autism

Rosenberg

Patterson

Angelaki

2015

Proc. Natl. Acad. Sci. U.S.A.

147

151

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Autism is a neurodevelopmental disorder that manifests as a heterogeneous set of social, cognitive, motor, and perceptual symptoms. This system-wide pervasiveness suggests that, rather than narrowly impacting individual systems such as affection or vision, autism may broadly alter neural computation. Here, we propose that alterations in nonlinear, canonical computations occurring throughout the brain may underlie the behavioral characteristics of autism. One such computation, called divisive normalization, balances a neuron's net excitation with inhibition reflecting the overall activity of the neuronal population. Through neural network simulations, we investigate how alterations in divisive normalization may give rise to autism symptomatology. Our findings show that a reduction in the amount of inhibition that occurs through divisive normalization can account for perceptual consequences of autism, consistent with the hypothesis of an increased ratio of neural excitation to inhibition (E/I) in the disorder. These results thus establish a bridge between an E/I imbalance and behavioral data on autism that is currently absent. Interestingly, our findings implicate the context-dependent, neuronal milieu as a key factor in autism symptomatology, with autism reflecting a less "social" neuronal population. Through a broader discussion of perceptual data, we further examine how altered divisive normalization may contribute to a wide array of the disorder's behavioral consequences. These analyses show how a computational framework can provide insights into the neural basis of autism and facilitate the generation of falsifiable hypotheses. A computational perspective on autism may help resolve debates within the field and aid in identifying physiological pathways to target in the treatment of the disorder.A utism is a neurodevelopmental disorder that is dramatically increasing in prevalence (Fig. 1). Recent data place the number of children being diagnosed with autism in the United States at 1 in 68, more than doubling in the last decade (1-4). The disorder is highly pervasive, affecting individuals at cognitive, motor, and perceptual levels. It is furthermore a "spectrum disorder," with symptoms that manifest in varying degrees across individuals. This heterogeneity presents significant challenges to establishing a comprehensive characterization of the disorder.Research investigating the genetic and molecular basis of autism implicates over 100 genes (5), many of which are involved in synaptic development and function (6-8). As such, one prominent hypothesis is that autism arises from a neurophysiological excitation-to-inhibition (E/I) imbalance (9, 10). However, the connection between an E/I imbalance and the behavioral characteristics of the disorder remains unclear. Considering the pervasive nature of autism, and the covariance of loosely related symptoms (11-14), one possibility is that an E/I imbalance widely affects neural computation, in turn giving rise to the broad behavioral symptoms recognized as autism.Here,...

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Section: Significancementioning

confidence: 91%

A computational perspective on autism

Rosenberg

Patterson

Angelaki

2015

Proc. Natl. Acad. Sci. U.S.A.

147

151

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“…The ASD group was all male while seven out of the 11 control group were male. The unequal distribution of sex for the ASD donors reflects the availability of postmortem brain tissue (Casanova et al 2009; Fatemi et al 2014; Fung et al 2014). The postmortem interval was 14.8 h for ASD and 17.1 h for control group.…”

Section: Methodsmentioning

confidence: 99%

Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum

Azmitia

Saccomano

Alzoobaee

et al. 2015

J Autism Dev Disord

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In the current work, we conducted an immunocytochemical search for markers of ongoing neurogenesis (e.g. nestin) in auditory cortex from postmortem sections of autism spectrum disorder (ASD) and age-matched control donors. We found nestin labeling in cells of the vascular system, indicating blood vessels plasticity. Evidence of angiogenesis was seen throughout superior temporal cortex (primary auditory cortex), fusiform cortex (face recognition center), pons/midbrain and cerebellum in postmortem brains from ASD patients but not control brains. We found significant increases in both nestin and CD34, which are markers of angiogenesis localized to pericyte cells and endothelial cells, respectively. This labeling profile is indicative of splitting (intussusceptive), rather than sprouting, angiogenesis indicating the blood vessels are in constant flux rather than continually expanding.

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“…In ASD, abnormalities have been found in many of the components of this system. For example found reductions in GABA A receptor density in parietal, cerebellar and superior frontal regions in ASD (see also Blatt et al, 2001;Fatemi et al, 2014, Oblak et al, 2011, 2010, and AMPA-type glutamate receptor density was found to be reduced in the cerebellum of individuals with ASD (Purcell, Jeon, Zimmerman, Blue, & Pevsner, 2001). There is also evidence that the synthesis of GABA and glutamate is altered in ASD.…”

Section: Cellular Abnormalitiesmentioning

confidence: 97%

Measuring neural excitation and inhibition in autism: Different approaches, different findings and different interpretations

2016

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The balance of neural excitation and inhibition (E/I balance) is often hypothesised to be altered in autism spectrum disorder (ASD). One widely held view is that excitation levels are elevated relative to inhibition in ASD. Understanding whether, and how, E/I balance may be altered in ASD is important given the recent interest in trialling pharmacological interventions for ASD which target inhibitory neurotransmitter function.Here we provide a critical review of evidence for E/I balance in ASD. We conclude that data from a number of domains provides support for alteration in excitation and inhibitory neurotransmission in ASD, but when considered collectively, the available literature provide little evidence to support claims for either a net increase in excitation or a net increase in inhibition. Strengths and limitations of available techniques are considered, and directions for future research discussed.3

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Downregulation of GABAA Receptor Protein Subunits α6, β2, δ, ε, γ2, θ, and ρ2 in Superior Frontal Cortex of Subjects with Autism

Cited by 78 publications

References 74 publications

A computational perspective on autism

A computational perspective on autism

Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum

Measuring neural excitation and inhibition in autism: Different approaches, different findings and different interpretations

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